Vasodilator Drugs: Chronic Vasodilator Therapy - Hydralazine
General (including evidence of efficacy)
Chronic vasodilator therapy
With the introduction of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-adrenergic blockers, chronic vasodilator therapy has moved into a second- or third-level therapy for chronic heart failure. At the present time, chronic oral vasodilator therapy consists of hydralazine, a nitrate preparation, and a combination of these two groups.
Differences between drugs within the class
Hydralazine is a hydrazinophthalazine compound, which has vasodilatory-relaxation effects on systemic and to a certain extent, pulmonary arterioles.
The general dose range for the oral administration of hydralazine in heart failure is 25 to 100 mg orally every 6 to 8 hours. It is completely and rapidly absorbed with peak plasma concentrations occurring 30 to 90 minutes after ingestion; 80% to 90% of hydralazine is cleared by the liver and the remainder by renal excretion.
More than 75% is protein bound with an elimination half-life of 1 to 2 hours. Heart failure may modify its pharmacokinetics, but this has not been clarified.
The cellular mechanism of action remains unclear, but hydralazine likely retards the release of calcium in arteriolar smooth muscle. In the setting of heart failure, hydralazine's augmentation of cardiac contractility is secondary to enhanced sympathetic nervous system activity and tone, and a direct inotropic action on cardiac myocytes.
Hydralazine acts primarily as a systemic vasodilator and as such, delivers mostly afterload reduction to the left ventricle with a modest effect on preload or ventricular diastolic filling pressure. Hydralazine reduces systemic and pulmonary vascular resistance with a concomitant rise in cardiac output. The increase in stroke volume and cardiac output is, in part, related to the direct inotropic effect on the myocardium and the activation of sympathetic tone. The drop in pulmonary capillary wedge pressure is secondary to the reduction of mitral regurgitation and the ventricular response to afterload reduction.
Hydralazine increases renal blood flow, but elicits little change in glomerular filtration rate and overall renal function.
Hydralazine, because of its inotropic properties and ability to augment sympathetic tone, can increase myocardial oxygen consumption more than the accompanying rise in coronary blood flow and myocardial perfusion. For this reason, hydralazine is generally administered with caution or with a nitrate preparation in patients with occlusive coronary artery disease.
Indications and contraindications
Hydralazine is generally used in combination with an oral nitrate preparation. It is employed in patients who remain symptomatic from heart failure following optimization of ACE inhibitors, ARBs, diuretics, and beta-blockers.
In the absence of occlusive coronary artery disease and for the patient who has difficulty taking a nitrate because of intolerable side effects, hydralazine can be used as a primary afterload reducing agent, particularly if the left ventricular systolic dysfunction is accompanied by substantial mitral regurgitation. Hydralazine in dose incrementation can be effective in weaning patients, who appear to be dobutamine-dependent, off dobutamine.
Most patients tolerate hydralazine reasonably well when starting at a low dose (25 to 50 mg), with gradual dose incrementation over time. Headaches, flushing, myalgia, and gastrointestinal symptoms may require dose reduction or discontinuation. In the setting of heart failure with adequate or high left ventricular filling pressure, hypotension is rare and portends a poor prognosis (implies loss of cardiac contractile reserve). A lupus presentation or reaction is unusual in heart failure despite the high doses often employed (>100 every 6 to 8 hours).
The alternative approaches include optimization of ACE inhibitors, ARBs, beta-blockers, and nitrates. Vasodilators closely related to hydralazine (e.g., minoxidil) have not been adequately studied in heart failure.[
What's the Evidence?
Leier, CV, Magorien, RD, Desch, CE, Thompson, MJ, Unverferth, DV. "Hydralazine and isosorbide dinitrate: Comparative central and regional hemodynamic effects when administered alone or in combination". Circulation. vol. 63. 1981. pp. 102-109.
Leier, CV, Desch, CE, Magorien, RD, Triffon, DW, Unverferth, DV, Boudoulas, H, Lewis, RP. " Positive inotropic effects of hydralazine in human subjects: Comparison with prazosin in the setting of congestive heart failure". Am J Cardiol. vol. 46. 1980. pp. 1039-1044.
Binkley, PF, Starling, RC, Hammer, DF, Leier, CV. "Usefulness of hydralazine to withdraw from dobutamine in severe congestive heart failure". Am J Cardiol. vol. 69. 1191. pp. 1103-1106.(These papers present the basic clinical properties and responses to hydralazine in systolic heart failure.)
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